Polymeric carriers for amphotericin B: in vitro activity, toxicity and therapeutic efficacy against systemic candidiasis in neutropenic mice
Objective: To study the toxicity and activity of two new amphotericin B formulations: poly(ε-caprolactone) nanospheres coated with poloxamer 188 (AmB-NP) and mixed micelles with the same surfactant (AmB-MM). Materials and methods: The toxicity of these formulations was evaluated in erythrocytes, J...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | info:eu-repo/semantics/article |
| Language: | eng |
| Published: |
Oxford University Press
2011
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10171/19187 |
| _version_ | 1793400196025024512 |
|---|---|
| author | Espuelas, S. (Socorro) Legrand, P. (P.) Campanero, M.A. (Miguel Angel) Appel, M. (M.) Cheron, M. (M.) Gamazo, C. (Carlos) Barratt, G. (G.) Irache, J.M. (Juan Manuel) |
| author_facet | Espuelas, S. (Socorro) Legrand, P. (P.) Campanero, M.A. (Miguel Angel) Appel, M. (M.) Cheron, M. (M.) Gamazo, C. (Carlos) Barratt, G. (G.) Irache, J.M. (Juan Manuel) |
| author_sort | Espuelas, S. (Socorro) |
| collection | DSpace |
| description | Objective: To study the toxicity and activity of two new amphotericin B formulations: poly(ε-caprolactone)
nanospheres coated with poloxamer 188 (AmB-NP) and mixed micelles with the same surfactant (AmB-MM).
Materials and methods: The toxicity of these formulations was evaluated in erythrocytes, J774.2 macrophages
and LLCPK1 renal cells, as well as in mice. Activity was determined in clinical isolates and in neutropenic
mice. Mice were made neutropenic with 5-fluorouracil, infected with Candida albicans and treated
with the antifungal formulations for three consecutive days. AmB association in cells and accumulation in
kidneys and liver of animals was quantified by HPLC.
Results: Both formulations decreased between 8- and 10-fold the MIC of the polyene against clinical isolates
of C. albicans. However, their activity was lower than or equal to that of AmB-deoxycholate when it was
assessed against C. albicans-infected macrophages. When given as a single intravenous dose in mice,
AmB-MM and AmB-NP had an LD50 of 9.8 and 18.6 mg/kg, respectively, compared with 4 mg/kg for AmBdeoxycholate.
Comparison of residual infection burdens in the liver and kidneys showed that AmB-deoxycholate
(0.5 mg/kg) was more effective and faster in eradicating yeast cells than polymeric formulations.
This fact can be related to a lower AmB accumulation inside macrophages and in liver and kidneys (about 1.5
mg drug/g tissue) of mice, compared with those detected for AmB-deoxycholate (4 mg drug/g). Overall, the
efficacy of these formulations at 2 mg/kg was equal to that of AmB-deoxycholate at 0.5 mg/kg.
Conclusions: AmB-MM and AmB-NP decreased the in vivo antifungal activity of AmB, and higher concentrations
were therefore necessary to obtain a similar therapeutic effect. However, these higher concentrations
were achievable owing to the reduced toxicity of these formulations. |
| format | info:eu-repo/semantics/article |
| id | oai:dadun.unav.edu:10171-19187 |
| institution | Universidad de Navarra |
| language | eng |
| publishDate | 2011 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oai:dadun.unav.edu:10171-191872020-03-03T19:48:40Z Polymeric carriers for amphotericin B: in vitro activity, toxicity and therapeutic efficacy against systemic candidiasis in neutropenic mice Espuelas, S. (Socorro) Legrand, P. (P.) Campanero, M.A. (Miguel Angel) Appel, M. (M.) Cheron, M. (M.) Gamazo, C. (Carlos) Barratt, G. (G.) Irache, J.M. (Juan Manuel) Amphotericin B Candida albicans Micelles Nanospheres Poloxamer Objective: To study the toxicity and activity of two new amphotericin B formulations: poly(ε-caprolactone) nanospheres coated with poloxamer 188 (AmB-NP) and mixed micelles with the same surfactant (AmB-MM). Materials and methods: The toxicity of these formulations was evaluated in erythrocytes, J774.2 macrophages and LLCPK1 renal cells, as well as in mice. Activity was determined in clinical isolates and in neutropenic mice. Mice were made neutropenic with 5-fluorouracil, infected with Candida albicans and treated with the antifungal formulations for three consecutive days. AmB association in cells and accumulation in kidneys and liver of animals was quantified by HPLC. Results: Both formulations decreased between 8- and 10-fold the MIC of the polyene against clinical isolates of C. albicans. However, their activity was lower than or equal to that of AmB-deoxycholate when it was assessed against C. albicans-infected macrophages. When given as a single intravenous dose in mice, AmB-MM and AmB-NP had an LD50 of 9.8 and 18.6 mg/kg, respectively, compared with 4 mg/kg for AmBdeoxycholate. Comparison of residual infection burdens in the liver and kidneys showed that AmB-deoxycholate (0.5 mg/kg) was more effective and faster in eradicating yeast cells than polymeric formulations. This fact can be related to a lower AmB accumulation inside macrophages and in liver and kidneys (about 1.5 mg drug/g tissue) of mice, compared with those detected for AmB-deoxycholate (4 mg drug/g). Overall, the efficacy of these formulations at 2 mg/kg was equal to that of AmB-deoxycholate at 0.5 mg/kg. Conclusions: AmB-MM and AmB-NP decreased the in vivo antifungal activity of AmB, and higher concentrations were therefore necessary to obtain a similar therapeutic effect. However, these higher concentrations were achievable owing to the reduced toxicity of these formulations. 2011-10-22T16:56:52Z 2011-10-22T16:56:52Z 2003 info:eu-repo/semantics/article https://hdl.handle.net/10171/19187 eng info:eu-repo/semantics/openAccess application/pdf Oxford University Press |
| spellingShingle | Amphotericin B Candida albicans Micelles Nanospheres Poloxamer Espuelas, S. (Socorro) Legrand, P. (P.) Campanero, M.A. (Miguel Angel) Appel, M. (M.) Cheron, M. (M.) Gamazo, C. (Carlos) Barratt, G. (G.) Irache, J.M. (Juan Manuel) Polymeric carriers for amphotericin B: in vitro activity, toxicity and therapeutic efficacy against systemic candidiasis in neutropenic mice |
| title | Polymeric carriers for amphotericin B: in vitro activity, toxicity and therapeutic efficacy against systemic candidiasis in neutropenic mice |
| title_full | Polymeric carriers for amphotericin B: in vitro activity, toxicity and therapeutic efficacy against systemic candidiasis in neutropenic mice |
| title_fullStr | Polymeric carriers for amphotericin B: in vitro activity, toxicity and therapeutic efficacy against systemic candidiasis in neutropenic mice |
| title_full_unstemmed | Polymeric carriers for amphotericin B: in vitro activity, toxicity and therapeutic efficacy against systemic candidiasis in neutropenic mice |
| title_short | Polymeric carriers for amphotericin B: in vitro activity, toxicity and therapeutic efficacy against systemic candidiasis in neutropenic mice |
| title_sort | polymeric carriers for amphotericin b: in vitro activity, toxicity and therapeutic efficacy against systemic candidiasis in neutropenic mice |
| topic | Amphotericin B Candida albicans Micelles Nanospheres Poloxamer |
| url | https://hdl.handle.net/10171/19187 |
| work_keys_str_mv | AT espuelasssocorro polymericcarriersforamphotericinbinvitroactivitytoxicityandtherapeuticefficacyagainstsystemiccandidiasisinneutropenicmice AT legrandpp polymericcarriersforamphotericinbinvitroactivitytoxicityandtherapeuticefficacyagainstsystemiccandidiasisinneutropenicmice AT campaneromamiguelangel polymericcarriersforamphotericinbinvitroactivitytoxicityandtherapeuticefficacyagainstsystemiccandidiasisinneutropenicmice AT appelmm polymericcarriersforamphotericinbinvitroactivitytoxicityandtherapeuticefficacyagainstsystemiccandidiasisinneutropenicmice AT cheronmm polymericcarriersforamphotericinbinvitroactivitytoxicityandtherapeuticefficacyagainstsystemiccandidiasisinneutropenicmice AT gamazoccarlos polymericcarriersforamphotericinbinvitroactivitytoxicityandtherapeuticefficacyagainstsystemiccandidiasisinneutropenicmice AT barrattgg polymericcarriersforamphotericinbinvitroactivitytoxicityandtherapeuticefficacyagainstsystemiccandidiasisinneutropenicmice AT irachejmjuanmanuel polymericcarriersforamphotericinbinvitroactivitytoxicityandtherapeuticefficacyagainstsystemiccandidiasisinneutropenicmice |